Paquinimod (ABR 25757)
(Synonyms: 帕奎莫德; ABR 25757) 目录号 : GC31346
Paquinimod (ABR-215757) binds S100A9 and inhibits its interaction with TLR4/MD2 and RAGE.
Cas No.:248282-01-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Tissue experiment [1]: | |
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Tissue |
Human synovium |
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Preparation Method |
Incubated osteoarthritis (OA) synovium with human S100A916 and paquinimod and measured the protein release. |
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Reaction Conditions |
350 µM paquinimod;30 min preincubated |
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Applications |
S100A9 clearly upregulated IL-6, IL-8 and TNF-α protein levels in OA synovia, and addition of paquinimodsignificantly inhibited this upregulation for IL-6 and IL-8, but not TNF-α. |
| Animal experiment [2]: | |
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Animal models |
IQAD Tg C57Bl/6 mice |
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Preparation Method |
Mice were treated with 10 mg/kg/day paquinimod, added into the drinking water starting 7 days prior to the addition of DSS and continued during the DSS regimen. Control mice received the same dose of paquinimod for 14 days. In all experiments, water was changed twice a week. |
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Dosage form |
10 mg/kg/day paquinimod;14days;added into the drinking water |
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Applications |
Mice prophylactically treated with paquinimod exhibited detectable but mitigated signs of colitis, as determined by a reduced trend in weight loss, reduced colonic shortening and inflammation in the colons compared to DSS-only treated mice. Paquinimod treatment also prevented the upregulation of Lcn2 and S100A8/A9 in the brain in DSS-treated mice. |
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References: [1].Schelbergen RF, Geven EJ, et,al.Prophylactic treatment with S100A9 inhibitor paquinimod reduces pathology in experimental collagenase-induced osteoarthritis. Ann Rheum Dis. 2015 Dec;74(12):2254-8. doi: 10.1136/annrheumdis-2014-206517. Epub 2015 May 12. PMID: 25969431. [2]. Talley S, Valiauga R, et,al.DSS-induced inflammation in the colon drives a proinflammatory signature in the brain that is ameliorated by prophylactic treatment with the S100A9 inhibitor paquinimod. J Neuroinflammation. 2021 Nov 10;18(1):263. doi: 10.1186/s12974-021-02317-6. PMID: 34758843; PMCID: PMC8578918. |
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Paquinimod (ABR-215757) binds S100A9 and inhibits its interaction with TLR4/MD2 and RAGE[1-2].
The addition of paquinimod(350 μM paquinimod;30 min preincubated) significantly inhibited the up-regulated levels of IL-6 and IL-8 protein in synovium due to S100A9, but had no inhibitory effect on TNF-α[7].
Mice prophylactically treated with paquinimod(10 mg/kg/day;14days;added into the drinking water) exhibited detectable but mitigated signs of colitis, as determined by a reduced trend in weight loss, reduced colonic shortening and inflammation in the colons compared to DSS-only treated mice. Paquinimod treatment also prevented the upregulation of Lcn2 and S100A8/A9 in the brain in DSS-treated mice[3]. In a meningitis model, MRP14-deficient mice showed a better resolution of inflammation during antibiotic therapy. Treatment with the MRP14 antagonist paquinimod(10 mg/kg) reduced inflammation and disease severity significantly, reaching levels comparable to those achieved after genetic depletion of MRP14[4]. Preventive treatment with the paquinimod (ABR-215757) (25 mg/kg;5days;added into the drinking water) during the first 5 days after induction of experimental autoimmune encephalomyelitis is sufficient to significantly ameliorate disease symptoms[5]. Paquinimod treatment can significantly inhibit progression of insulitis to T1D in the NOD mouse[6].
References:
[1]. Bj?rk P, Bj?rk A,et,al. Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to quinoline-3-carboxamides. PLoS Biol. 2009 Apr 28;7(4):e97. doi: 10.1371/journal.pbio.1000097. PMID: 19402754; PMCID: PMC2671563.
[2]. Gong H, Su WJ, et,al.Hippocampal Mrp8/14 signaling plays a critical role in the manifestation of depressive-like behaviors in mice. J Neuroinflammation. 2018 Sep 4;15(1):252. doi: 10.1186/s12974-018-1296-0. PMID: 30180864; PMCID: PMC6122683.
[3]. Talley S, Valiauga R, et,al.DSS-induced inflammation in the colon drives a proinflammatory signature in the brain that is ameliorated by prophylactic treatment with the S100A9 inhibitor paquinimod. J Neuroinflammation. 2021 Nov 10;18(1):263. doi: 10.1186/s12974-021-02317-6. PMID: 34758843; PMCID: PMC8578918.
[4]. Wache C, Klein M, et,al.Myeloid-related protein 14 promotes inflammation and injury in meningitis. J Infect Dis. 2015 Jul 15;212(2):247-57. doi: 10.1093/infdis/jiv028. Epub 2015 Jan 20. PMID: 25605866.
[5]. Helmersson S, Sundstedt A, et,al.Amelioration of experimental autoimmune encephalomyelitis by the quinoline-3-carboxamide paquinimod: reduced priming of proinflammatory effector CD4(+) T cells. Am J Pathol. 2013 May;182(5):1671-80. doi: 10.1016/j.ajpath.2013.01.032. Epub 2013 Mar 16. PMID: 23506849.
[6]. Tahvili S, T?rngren M, et,al. Paquinimod prevents development of diabetes in the non-obese diabetic (NOD) mouse. PLoS One. 2018 May 9;13(5):e0196598. doi: 10.1371/journal.pone.0196598. PMID: 29742113; PMCID: PMC5942776.
[7]. Schelbergen RF, Geven EJ, et,al.Prophylactic treatment with S100A9 inhibitor paquinimod reduces pathology in experimental collagenase-induced osteoarthritis. Ann Rheum Dis. 2015 Dec;74(12):2254-8. doi: 10.1136/annrheumdis-2014-206517. Epub 2015 May 12. PMID: 25969431.
Paquinimod (ABR-215757) 结合 S100A9 并抑制其与 TLR4/MD2 和 RAGE 的相互作用[1-2]。
添加帕喹莫德（350 μM 帕喹莫德；30 分钟预孵育）可显着抑制 S100A9 引起的滑膜中 IL-6 和 IL-8 蛋白水平上调，但对 TNF-α 无抑制作用 [7].
用帕喹莫德（10 毫克/千克/天；14 天；添加到饮用水中）进行预防性治疗的小鼠表现出可检测到但减轻的结肠炎迹象，这是由体重减轻趋势减少、结肠缩短和结肠炎症减少来确定的与仅接受 DSS 治疗的小鼠相比。 Paquinimod 治疗还阻止了 DSS 治疗小鼠大脑中 Lcn2 和 S100A8/A9 的上调[3]。在脑膜炎模型中，MRP14 缺陷小鼠在抗生素治疗期间表现出更好的炎症消退。使用 MRP14 拮抗剂帕喹莫德 (10 mg/kg) 治疗可显着降低炎症和疾病严重程度，达到与 MRP14 基因缺失后达到的水平相当[4]。在诱导实验性自身免疫性脑脊髓炎后的前 5 天内，使用帕喹莫德 (ABR-215757)（25 mg/kg；5 天；添加到饮用水中）进行预防性治疗足以显着改善疾病症状[5]。帕喹莫德治疗可显着抑制 NOD 小鼠胰岛炎进展为 T1D[6]。
| Cas No. | 248282-01-1 | SDF | |
| 别名 | 帕奎莫德; ABR 25757 | ||
| Canonical SMILES | O=C(C1=C(O)C2=C(C=CC=C2CC)N(C)C1=O)N(CC)C3=CC=CC=C3 | ||
| 分子式 | C21H22N2O3 | 分子量 | 350.41 |
| 溶解度 | DMSO : ≥ 125 mg/mL (356.72 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.8538 mL | 14.269 mL | 28.538 mL |
| 5 mM | 0.5708 mL | 2.8538 mL | 5.7076 mL |
| 10 mM | 0.2854 mL | 1.4269 mL | 2.8538 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
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1. 首先保证母液是澄清的；
2.
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DSS-induced inflammation in the colon drives a proinflammatory signature in the brain that is ameliorated by prophylactic treatment with the S100A9 inhibitor paquinimod
J Neuroinflammation.2021 Nov 10;18(1):263.PMID: 34758843DOI: 10.1186/s12974-021-02317-6
Background: Inflammatory bowel disease (IBD) is established to drive pathological sequelae in organ systems outside the intestine, including the central nervous system (CNS). Many patients exhibit cognitive deficits, particularly during disease flare. The connection between colonic inflammation and neuroinflammation remains unclear and characterization of the neuroinflammatory phenotype in the brain during colitis is ill-defined. Methods: Transgenic mice expressing a bioluminescent reporter of active caspase-1 were treated with 2% dextran sodium sulfate (DSS) for 7 days to induce acute colitis, and colonic, systemic and neuroinflammation were assessed. In some experiments, mice were prophylactically treated with paquinimod (ABR-215757) to inhibit S100A9 inflammatory signaling. As a positive control for peripheral-induced neuroinflammation, mice were injected with lipopolysaccharide (LPS). Colonic, systemic and brain inflammatory cytokines and chemokines were measured by cytokine bead array (CBA) and Proteome profiler mouse cytokine array. Bioluminescence was quantified in the brain and caspase activation was confirmed by immunoblot. Immune cell infiltration into the CNS was measured by flow cytometry, while light sheet microscopy was used to monitor changes in resident microglia localization in intact brains during DSS or LPS-induced neuroinflammation. RNA sequencing was performed to identify transcriptomic changes occurring in the CNS of DSS-treated mice. Expression of inflammatory biomarkers were quantified in the brain and serum by qRT-PCR, ELISA and WB. Results: DSS-treated mice exhibited clinical hallmarks of colitis, including weight loss, colonic shortening and inflammation in the colon. We also detected a significant increase in inflammatory cytokines in the serum and brain, as well as caspase and microglia activation in the brain of mice with ongoing colitis. RNA sequencing of brains isolated from DSS-treated mice revealed differential expression of genes involved in the regulation of inflammatory responses. This inflammatory phenotype was similar to the signature detected in LPS-treated mice, albeit less robust and transient, as inflammatory gene expression returned to baseline following cessation of DSS. Pharmacological inhibition of S100A9, one of the transcripts identified by RNA sequencing, attenuated colitis severity and systemic and neuroinflammation. Conclusions: Our findings suggest that local inflammation in the colon drives systemic inflammation and neuroinflammation, and this can be ameliorated by inhibition of the S100 alarmin, S100A9.
Induction of alarmin S100A8/A9 mediates activation of aberrant neutrophils in the pathogenesis of COVID-19
Cell Host Microbe.2021 Feb 10;29(2):222-235.PMID: 33388094DOI: 10.1016/j.chom.2020.12.016
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic poses an unprecedented public health crisis. Evidence suggests that SARS-CoV-2 infection causes dysregulation of the immune system. However, the unique signature of early immune responses remains elusive. We characterized the transcriptome of rhesus macaques and mice infected with SARS-CoV-2. Alarmin S100A8 was robustly induced in SARS-CoV-2-infected animal models as well as in COVID-19 patients. Paquinimod, a specific inhibitor of S100A8/A9, could rescue the pneumonia with substantial reduction of viral loads in SARS-CoV-2-infected mice. Remarkably, Paquinimod treatment resulted in almost 100% survival in a lethal model of mouse coronavirus infection using the mouse hepatitis virus (MHV). A group of neutrophils that contributes to the uncontrolled pathological damage and onset of COVID-19 was dramatically induced by coronavirus infection. Paquinimod treatment could reduce these neutrophils and regain anti-viral responses, unveiling key roles of S100A8/A9 and aberrant neutrophils in the pathogenesis of COVID-19, highlighting new opportunities for therapeutic intervention.
Paquinimod prevents development of diabetes in the non-obese diabetic (NOD) mouse
PLoS One.2018 May 9;13(5):e0196598.PMID: 29742113DOI: 10.1371/journal.pone.0196598
Quinoline-3-carboxamides (Q compounds) are immunomodulatory compounds that have shown efficacy both in autoimmune disease and cancer. We have in here investigated the impact of one such compound, paquinimod, on the development of diabetes in the NOD mouse model for type I diabetes (T1D). In cohorts of NOD mice treated with paquinimod between weeks 10 to 20 of age and followed up until 40 weeks of age, we observed dose-dependent reduction in incidence of disease as well as delayed onset of disease. Further, in contrast to untreated controls, the majority of NOD mice treated from 15 weeks of age did not develop diabetes at 30 weeks of age. Importantly, these mice displayed significantly less insulitis, which correlated with selectively reduced number of splenic macrophages and splenic Ly6Chi inflammatory monocytes at end point as compared to untreated controls. Collectively, these results demonstrate that paquinimod treatment can significantly inhibit progression of insulitis to T1D in the NOD mouse. We propose that the effect of paquinimod on disease progression may be related to the reduced number of these myeloid cell populations. Our finding also indicates that this compound could be a candidate for clinical development towards diabetes therapy in humans. Conflict of interest statement Competing Interests: TL was a part-time employee and owns shares in Active Biotech AB. MT is an employee and has ownership interests in Active Biotech AB. FI receives a research grant from Active Biotech AB. There are no further patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.